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Infect. Immun. doi:10.1128/IAI.00369-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Fibrotic response as a distinguishing feature of resistance and susceptibility to pulmonary infection with Mycobacterium tuberculosis in mice

Centre for the Study of Host Resistance, Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3G 1Y6; Biotechnology Research Institute, National Research Council of Canada, Montréal, Québec, Canada; Trudeau Institute, Saranac Lake, NY, USA

^* To whom correspondence should be addressed. Email: philippe.gros{at}mcgill.ca.

	Abstract

The differential susceptibility of inbred mouse strains DBA/2J (D2; susceptible) and C57BL/6J (B6; resistant) to pulmonary tuberculosis following aerosol infection is under complex genetic control. In this report, transcriptional profiling with RNA from Mycobacterium tuberculosis-infected lungs was used to investigate the physiological response, cell type and biochemical pathways underlying differential susceptibility to infection. Statistical analysis of cDNA based microarrays revealed that 1097 transcripts showed statistically significant changes in abundance (fold change of 1.5X) in at least one of the four experimental group comparisons [B6(Day0)/D2(Day0), B6(Day90)/D2(Day90), B6(Day90)/B6(Day0), or D2(Day90)/D2(Day0)]. A group of genes showing very high degree of significance (fold change of 2.0X) displayed enrichment for transcripts associated with tissue remodeling and fibrotic response. The differential expression of fibrotic response genes (Sparc, Col1a1, Col1a2, Col4a1, and Col4a2) in the infected lungs of the two mouse strains was validated by another microarray platform (Affymetrix oligos chips) and by RT-PCR. Furthermore, the different expression of additional genes known to be associated with fibrosis (Mmp2, Timp1, and Arg1) was also validated by these approaches. Overall, these results identify differential fibrotic response as a pathological basis for the high susceptibility of D2 mice to pulmonary tuberculosis.